Alcohol dependence is a chronic, relapsing disorder and the development of medications for this disorder has been based on a systematic understanding of the neurochemical processes mediating alcohol drinking behaviors. There is extensive evidence for a role for the glutamatergic and opioidergic systems in alcohol reward processes. In CTNA1 we showed for the first time that the efficacy of in reducing drinking is only observed in drinkers with a positive family history of alcoholism (FHP) and not in those with a negative family history of alcoholism (FHN); interestingly, this reduction in drinking was accompanied by very modest reductions in alcohol craving and no effects on alcohol-induced stimulation. In CTNA2 we conducted a similar examination using the glutatmatergic agent memantine, and again observed effects only in FHP but not in FHN drinkers; interestingly memantine appears to reduce alcohol stimulation and alcohol craving with modest effects on alcohol drinking. This exciting evidence suggests that glutamatergic and opioidergic agents may target different behavioral processes involved in alcohol drinking. Habitual alcohol use in alcohol dependent heavy drinkers may be dependent not just on continued alcohol reward but also on conditioned incentive processes, like cue-induced craving and automated motivational tendencies, which are mediated by complex interactions between different neurochemical processes, and could be targeted differentially by memantine and naltrexone. In CTNA3 we will conduct a proof of concept Phase I evaluation to examine the effect of combined treatment with naltrexone and memantine on alcohol drinking and alcohol reward as measured using alcohol-induced stimulation and craving, in non-treatment seeking, alcohol dependent, heavy drinkers with a positive family history of alcoholism. Exploratory aims will also evaluate the influence of these medications on automated motivational tendencies towards alcohol drinking and also examine the influences of novel behavioral (Pavlovian to Instrumental transfer task) and genetic (Striatally enriched phosphates Fyn kinas) predictors on treatment response.